Clostridium difficile (C. difficile) is a gram-positive, spore-forming anaerobe that infects the gut when the natural flora has been disrupted, primarily through antibiotic treatment. It is currently the leading cause of nosocomial infections in the United States, resulting in approximately 29,000 deaths per year and costing the US health care system an estimated $4.8 billion annually. Disease can range from asymptomatic colonization, to mild diarrhea, to life threatening pseudomembranous colitis and toxic megacolon. A hypervirulent strain of C. difficile is the cause of 30-day mortality in up to 15% of patients diagnosed with C. difficile infection (CDI). Current therapy involves removal of the offending antibiotic and starting vancomycin or metronidazole treatment, which can inhibit the reestablishment of beneficial endogenous flora while fighting infection. Despite therapy, recurrent disease is seen in 10-35% of patients after their initial case of CDI and in 35-65% of patients after primary reoccurrence, stressing the need for more effective therapies. It has been hypothesized that the degree of disease severity correlates with the intensity of the host response. Therefore, a better understanding of the mechanism by which immune response provides production is important to develop therapies that modulate the host inflammatory response as a novel way to treat disease.
Over the past decade, epidemic, hypervirulent strains of C. difficile (NAPI/027 strains) have emerged with higher relapse rates and increased resistance to antibiotics; the current standard of care to treat CDI (6, 8). These epidemic strains have acquired the expression of a third toxin, binary toxin (CDT), in addition to previously expressed Toxins A and B (TcdA and TcdB) (8). CDT is composed of two subunits: CDTb is the binding subunit and CDTa is the enzymatic subunit. To intoxicate host cells, CDTb associates with a host cell surface receptor, thought to be the lipolysis-stimulated lipoprotein receptor (LSR) (9) and the enzymatic CDTa subunit destabilizes of the cellular cytoskeleton through ADP-ribosylation of actin (8). Our lab has discovered that CDT toxin increases the virulence of epidemic NAPI/027 strains of C. difficile. Furthermore, we have shown that CDT is sensed by toll-like receptor 2 (TLR2) to mount a detrimental pro-inflammatory immune response (10). Interestingly, our studies showed that CDT mediated activation of the TLR2 pathway is pathogenic for the host during C. difficile infection as TLR2−/− mice are significantly protected from NAPI/027 associated mortality (See FIGS. 1-3).
There is a long felt need in the art for compositions and methods useful for preventing and treating C. difficile infections. The present invention satisfies this need.